Combination therapy for chronic hepatitis C infection

ABSTRACT

There is disclosed a method for treating chronic hepatitis C infection in patients in need of such treating comprising administering an amount of alpha interferon in association with an amount of ribavirin effective to treat chronic hepatitis C infection with the absence or substantial reduction of side effects associated with administration of ribavirin and alpha interferon.

Chronic infection with hepatitis C virus is an insidious andslow-progressing disease having a significant impact on the quality oflife. It can eventually result in cirrhosis of the liver, decompensatedliver disease and/or hepatocelluar carcinoma.

Alpha interferon monotherapy is commonly used to treat chronic hepatitisC infection. However this treatment is not always effective andsometimes results in intolerable side effects related to the dosage andduration of therapy. Ribavirin has been proposed as a monotherapytreatment for chronic hepatitis C infection (Thomas et al. AASLDAbstracts, Hepatology Vol. 20, NO. 4, Pt 2, Number 440, 1994). However,this monotherapy treatment has usually been found relatively ineffectiveand has its own undesirable side effects.

Combination therapy of alpha interferon and ribavirin has been proposed(Lai, et al. Symposium to the 9th Biennial Scientific Meeting AsianPacific Association for the Study of the Liver. 1994). Preliminaryresults suggest that the combination therapy may be more effective thaneither monotherapy. However at the proposed dosages, undesirable sideeffects have still been encountered.

There is a need for a method for treating chronic hepatitis C infectionwith a combination of alpha interferon and ribavirin in the substantialabsence of side effects normally associated with either compound.

SUMMARY OF THE INVENTION

This invention may be summarized as a method for treating chronichepatitis C infection in patients in need of such treating comprisingadministering an amount of alpha interferon in association with anamount of ribavirin effective to treat hepatitis C in the absence orsubstantial reduction of side effects associated with ribavirin andalpha interferon.

DETAILED DESCRIPTION

All references cited herein are incorporated herein by reference.

The term “alpha interferon” as used herein means the family of highlyhomologous species-specific proteins that inhibit viral replication andcellular proliferation and modulate immune response. Typical suitablealpha interferons include but are not limited to recombinant interferonalpha-2b such as Intron-A interferon available from ScheringCorporation, Kenilworth, N.J., recombinant interferon alpha-2a such asRoferon A interferon available from Hoffmann-La Roche, Nutley, N.J.,recombinant interferon alpha-2C such as Berofor alpha 2 interferonavailable from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield,Conn., interferon alpha-n1, a purified blend of natural alphainterferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon availablefrom Amgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixtureof natural alpha interferons made by Interferon Sciences and availablefrom the Purdue Frederick Co., Norwalk, Conn., under the AlferonTradename. The use of interferon alpha-2a or alpha 2b is preferred.Since interferon alpha 2b, among all interferons, has the broadestapproval throughout the world for treating chronic hepatitis Cinfection, it is most preferred. The manufacture of interferon alpha 2bis described in U.S. Pat. No. 4,530,901. Of course the term alphainterferon includes the obvious equivalents thereto such as certain betainterferons known to have properties similar to alpha interferon.

Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., isdescribed in the Merck Index, compound No. 8199, Eleventh Edition. Itsmanufacture and formulation is described in U.S. Pat. No. 4,211,771.

A person suffering from chronic hepatitis C infection may exhibit one ormore of the following signs or symptoms:

(a) elevated ALT,

(b) positive test for anti-HCV antibodies,

(c) presence of HCV as demonstrated by a positive test for HCV-RNA,

(d) clinical stigmata of chronic liver disease,

(e) hepatocelluar damage.

To practice the invention, alpha interferon (hereinafter α-IFN) andribavirin are administered to the patient exhibiting one of more of theabove signs or symptoms in amounts sufficient to eliminate or at leastalleviate one or more of the signs or symptoms.

In prior treatment of chronic hepatitis C infection with α-IFNmonotherapy, α-IFN has been administered in dosages of about 3 to 10million International units (IU) thrice weekly. Alternatively 3 to 10million IU of α-IFN has been administered QOD (every other day) ordaily. The duration of the prior dosages has been from 12 to 24 months.This amount and duration of α-IFN monotherapy alleviates symptoms ofhepatitis C in some of the patients, but it causes undesirable sideeffects, e.g. flu-like symptoms, in some.

The preferred dosage of α-IFN for practicing the combination therapy ofthis invention is less than the prior amount, that is, less than 3million IU, more preferably 1 to 2 million IU administered thriceweekly, QOD, or daily. Alternatively the prior dosage of 3 to 10 millionIU administered thrice weekly, QOD or daily may be administered for ashorter duration, that is from 6 to 12 months. In either case, reducedside effects of α-IFN are expected, because of the reduced dosage orduration.

In prior treatment of chronic hepatitis C infection with ribavirinmonotherapy the usual dosage of ribavirin has been 1000 to 1200 mgadministered daily. This amount of ribavirin has been found to bemarginally effective in alleviating symptoms in a small percentage ofthe patients, but it causes the undesirable side effect of anemia.

The preferred dosage of ribavirin for practicing this invention is about400 to 1000 mg per day, more preferably 500 to 800. This daily dosagemay be administered once per day in a single dose or in divided doses.

The ribavirin is administered to the patient in association with theα-IFN, that is, the α-IFN dose is administered during the same period oftime that the patient receives doses of ribavirin. At present α-IFNformulations are not effective when administered orally, so thepreferred method of administering the α-IFN is parenterally, preferablyby subcutaneous, IV, or IM, injection. The ribavirin may be administeredorally in capsule or tablet form in association with the parenteraladministration of α-IFN. Of course other types of administration of bothmedicaments, as they become available are contemplated, such as by nasalspray, transdermally, by suppository, by sustained release dosage form,etc. Any form of administration will work so long as the proper dosagesare delivered without destroying the active ingredient.

The effectiveness of treatment may be determined by controlled clinicaltrials of the combination therapy versus monotherapy. The efficacy ofthe combination therapy in alleviating the signs and symptoms of chronichepatitis C infection and the frequency and severity of the side effectswill be compared with previous α-IFN and ribavirin monotherapy. Threepopulations suffering from chronic hepatitis C infection will beevaluated:

1. Patients previously untreated.

2. Patients previously treated with interferon or ribavirin and who hadsubsequently relapsed.

3. Patients who were non-responsive to previous treatment withinterferon or ribavirin.

The effectiveness of the combination therapy will be determined by theextent to which the previously described signs and symptoms of chronichepatitis are alleviated and the extent to which the normal side effectsof α-IFN and ribavirin are eliminated or substantially reduced. Thereduction or elimination of side effects will be accomplished by reduceddosage or dosage duration or both compared to the previousmonotherapies.

The normal side effects for α-IFN are listed in the package insert forINTRON-A interferon alfa-2b, recombinant, published October 1994 bySchering Corporation, Kenilworth N.J. The are primarily flu-likesymptoms such as fever, head ache, chills, myalgia, fatigue, etc. andcentral nervous system related symptoms such as depression, paresthesia,impaired concentration, etc.

The normal side effect of ribavirin is hemolytic anemia.

What is claimed is:
 1. A method for treating Hepatitis C infection in apatient comprising administering to said patient an amount of alphainterferon and an amount of ribavirin wherein the amount of alphainterferon administered is less than 3 million IU weekly, QOD or dailyand said alpha interferon consists of interferon alpha2.
 2. The methodof claim 1, wherein the amount of alpha interferon is administered 1 to2 million IU weekly, QOD or daily.
 3. The method of claim 2 wherein theamount of ribavirin administered is from 400 to 1000 mg per day.
 4. Themethod of claim 3 wherein the alpha interferon administered isinterferon alpha-2b.
 5. The method of claim 2 wherein the amount ofribavirin administered is from 500 to 800 mg per day.
 6. The method ofclaim 5 wherein the alpha interferon administered is interferonalpha-2b.
 7. The method of claim 2 wherein the alpha interferonadministered is interferon alpha-2b.
 8. The method of claim 1 whereinthe amount of ribavirin administered is from 400 to 1000 mg per day. 9.The method of claim 8 wherein the alpha interferon administered isinterferon alpha-2b.
 10. The method of claim 1 wherein the amount ofribavirin administered is from 500 to 800 mg per day.
 11. The method ofclaim 10 wherein the alpha interferon administered is interferonalpha-2b.
 12. The method of claim 1 wherein the alpha interferonadministered is interferon alpha-2b.
 13. The method of claim 1 whereinthe duration of the treatment is from 6 to 12 months.